TERNANOMED Sintesi della relazione

Final Report Summary - TERNANOMED (TERPENOYLATION: AN ORIGINAL CONCEPT FOR THE DISCOVERY OF NEW NANOMEDICINES)

Terpenoids are a group of natural compounds that are generally safe and extraordinary diverse in chemistry, structure and function. Most of them have physico-chemical characteristics able to adapt to a wide variety of biologically active compounds. Surprisingly, they have never been used previously as nanomaterials for drug delivery and targeting purposes. Thus, the current project aimed to develop terpenoid-based nanoassemblies to improve the treatment of severe diseases incl. cancer, and infectious diseases. The conceptual approach is to chemically link a terpene (either natural or synthetic) to a biologically active drug molecule in order to allow the resulting bioconjugate to self-assemble as nanoparticles in water. The expected results are: (i) a knowledge of structure/activity relationships which will allow the drug/polyterpene pair to self-assemble as nanoparticles, (ii) the design of new nanomedicines with high drug loading and absence of “burst” release, in order to propose (iii) a universal platform for the discovery of new nanomedicines.Concretely, the major achievements of the TERNANOMED project are as follows :

- We identified that the chemical linkage of the anticancer drug doxorubicin onto squalene, a natural lipid precursor of the cholesterol’s biosynthesis, led to the formation of squalenoyl doxorubicin nanoassemblies of 130-nm mean diameter, with an original “loop-train” structure. This unique nanomedicine demonstrates: (i) high drug payload, (ii) decreased toxicity of the coupled anticancer compound, (iii) improved therapeutic response, (iv) use of biocompatible transporter material, and (v) ease of preparation, all criteria that are not combined in the currently available nanodrugs. Taken together, these findings demonstrate that the squalenoylated doxorubicin nanoassemblies make tumor cells more sensitive to doxorubicin and reduce the cardiac toxicity (published in Proceedings of the Proceed. Natl. Acad. Sci. USA, 2014).

- We have developped a new strategy which relies on the controlled growth of a hydrophobic polymer from an anticancer drug-bearing macroalkoxyamine initiator , in order to position one chemotherapeutic at the extremity of each polymer chain. Due to the amphiphilic nature of the resulting drug-polymer conjugates, they spontaneously self-assemble in aqueous solution to form stable, narrowly-dispersed nanoparticles, which show significant anticancer activity both in vitro on various cancer cell lines as well as in vivo on human pancreatic tumor-bearing mice (Published in Angewandte Chemie Int. Edition, 2013).

- We have designed multifunctional nanoparticles combining in the same nanodevice either a drug and an imaging compound (ie., « theranostic » approach) or two drugs acting on complementary biological targets (ie., « multidrug » approach) (Published in ACS Nano, 2011 and ACS Nano, 2014).

- We have shown for the first time that the linkage of adenosine to squalene and subsequent construction as nanoassemblies allow the efficient administration of this molecule with significant pharmacological activity in a brain ischaemia and a spinal cord injury models. The demonstrated plasma reservoir effect of these Squalene-adenosine nanoassemblies allowed an improvement of the brain microcirculation, leading to a secondary parenchyma neuroprotection. Although further studies are needed to more precisely describe the exact therapeutic mechanism and to determine how dosage, administration frequency and timing of treatment with Squalene-adenosine nanoassemblies may affect the clinical outcome, this study opens a new exciting perspective for the treatment of severe neurological diseases where tissue ischaemia and/or trauma are involved (Published in Nature Nanotechnology, 2014).